INCREASED INOSITOL 1,4,5-TRISPHOSPHATE ACCUMULATION CORRELATES WITH AN UP-REGULATION OF BRADYKININ RECEPTORS IN ALZHEIMERS-DISEASE

An alteration in signal transduction systems in Alzheimer's disease (A D) would likely be of pathophysiological significance, because these p rocesses control normal brain functions. Previously, a diminished beta -adrenergic-mediated cyclic AMP response was found in cultured fibrobl asts from AD patients. Because cross-talk between the phosphoinositide and cyclic AMP pathways exists, the phosphoinositide cascade was stud ied under conditions that were similar to those for studying the cycli c AMP response. Cells from AD patients and age-matched controls respon ded to bradykinin (BK) and released inositol 1,4,5-trisphosphate [lns( 1,4,5)P-3] in a time- and dose-dependent manner. The level of lns(1,4, 5)P-3 increased rapidly and transiently in response to BK, peaked at 5 s, but still remained 116-132% above the basal level by 30 s. Althoug h the temporal patterns were similar in both groups, the lns(1,4,5)P-3 concentrations in AD fibroblasts were 73 and 89% above levels in the age-matched controls at 5 and 10 s, respectively. Prostaglandin E(1) a lso increased lns(1,4,5)P-3 formation, but this response was not diffe rent between the two groups. Although K-D (affinity) values for the BK receptor were similar in both control and AD cells, the number of BK receptors (B-max) was significantly elevated in AD fibroblasts (186.8 +/- 0.3 fmol/mg of protein) as compared with control fibroblasts (57.2 +/- 15.3 fmol/mg of protein). These results indicate that the elevate d lns(1,4,5)P-3 production in response to BK in AD fibroblasts is posi tively correlated with an increase in the receptor numbers.